Adaptive responses to the environment depend on the induction of the "stress response" in less differentiated organisms and cultured cells and the activation of the hypothalamic-pituitary-adrenal axis in animals and humans. This indicates that adrenal steroids and stress proteins play an important role in regulating cell survival in response to noxious stimuli. In an in vitro model, we analyzed the effects of either dexamethasone (DEX) treatment or environmental changes which can elicit a stress response, on the survival of cultured L-929 mouse fibroblasts exposed to the cytotoxic cytokine tumor necrosis factor alpha (TNF-alpha). DEX treatment produced a significant reduction in the apoptotic death of L-929 cells produced by TNF-alpha. Abrogation of the protective effect of DEX by actinomycin D and cycloheximide demonstrated that protection against TNF-alpha requires de novo synthesis of mRNA and proteins. The results were similar when L-929 cells were exposed to metabolic (serum starvation) or thermal (heat shock) stresses before TNF-alpha treatment. In both cases the stress process afforded significant protection against TNF-alpha cytotoxicity. Inhibition of mRNA and protein synthesis abrogated the protection exerted by stress (serum starvation) or produced massive death during the stress event (heat shock). The similarities in the protective activities of DEX and stress response and the reported interactions between heat shock proteins and glucocorticoid hormones suggest that stress proteins and glucocorticoids both belong to an ancient evolutionary pathway which controls cell survival.